HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation

Chronic low grade inflammation is one of the major metabolic disorders in case of obesity and associated pathologies. By its important secretion function, the role of adipose tissue in this metabolic low grade inflammation is well known. Recently, it was demonstrated that the alarmin high mobility group box protein 1 (HMGB1) is involved in obesity-related pathologies by its increased serum levels in obese compared to normal weight individuals, and by its proinflammatory effects. However, the role of HMGB1 on adipocytes inflammation is poorly documented and we propose to investigate this point. Primary culture of human subcutaneous adipocytes were performed from human adipose tissue samples. Cells were treated with recombinant HMGB1 with/without anti-TLR4 antibody and inhibitors of NF-kB and P38 MAPK. Supernatants were collected for IL-6 and MCP-1 ELISA. HMGB1 initiates Toll-like receptor 4 (TLR4)-dependent activation of inflammation through the downstream NF-kB and P38 MAPK signaling pathway to upregulate the secretion of the pro-inflammatory cytokine IL-6. HMGB1 has proinflammatory effects on adipocytes. This reinforces the role of TLR4 in adipose tissue inflammation and antagonizing the HMGB1 inflammatory pathway could bring on new therapeutic targets to counteract obesity-associated pathologies.

show abstract

“…14,15 In the same model, it has been reported that following TLR4 activation with LPS, the production of Figure 2. Signaling pathways of HMGB1.…”

Section: Discussionmentioning

confidence: 87%

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

et al. 2016

View full text Add to dashboard Cite

show abstract

“…HMGB1 can activate both TLRs (TLR2 and TLR4) and RAGE resulting in increased production of inflammatory mediators, but its main signaling pathway is activated through the interaction with RAGE (ref. 20 ) resulting in the activation of NF-κB further promoting inflammation 19 in a positive feedback loop and contributing thus to sustaining inflammation and angiogenesis under different pathological conditions. HMGB1 has been implicated in different disease states, including Alzheimer's disease, sepsis, ischemia-reperfusion, arthritis, and cancer and targeting the HMGB1 ligand or its receptor may have important potential application in the treatment of these diverse pathological conditions.…”

Section: Introductionmentioning

confidence: 99%

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

et al. 2016

View full text Add to dashboard Cite

Background and Aims. Activation of RAGE due to its increased expression in cancer cells or its stimulation by multiple ligands (AGEs, HMGB1, S100 proteins, etc.) may contribute to the proliferation, invasiveness of tumor cells and formation of distant metastases and also to the resistance of cancer to treatment. RAGE ligands could thus become both useful markers of disease severity and its outcome and, a potential therapeutic target. Conclusions. Better understanding of the role of RAGE activation in different types of cancer may help to define the role of ligand/RAGE antagonists as promising cancer treatment.

show abstract

“…Toll-like receptors (TLRs) are a family of pattern recognition receptors that play a major role in the recognition of pathogenassociated molecular patterns in innate immunity [8,9] . TLR4, as a cellular receptor for bacterial lipopolysaccharide (LPS), is by far the most extensively studied member of the TLR family.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling

et al. 2014

View full text Add to dashboard Cite

Aim: To investigate the therapeutic effects of resveratrol (RSV) on periodontitis in diabetic mice and to explore the underlying mechanisms in vitro. Methods: Experimental periodontitis was induced in db/db mice by ligature application of porphyromonas gingivalis. The mice were treated with RSV (20 mg/kg, po) daily for 4 weeks. Alveolar bone loss, proinflammatory cytokines and TLR4 expression in the gingival tissue were measured. Cultured gingival epithelial cells (GECs) were used for in vitro studies. The transcriptional activity of TLR4 downstream signaling was analyzed using Western blotting. Results: RSV administration significantly decreased the blood glucose levels, and ameliorated alveolar bone loss in db/db mice with experimental periodontitis. RSV administration also suppressed the high levels of IL-1β, IL-6, IL-8, TNF-α, and TLR4 in gingival tissue of the mice. In the GECs incubated in high glucose medium, TLR4 expression was substantially upregulated, which was partly blocked in the presence of RSV. Lipopolysaccharides markedly increased the expression and secretion of IL-1β, IL-6, IL-8, and TNF-α in the GECs cultured in high glucose medium, which was also partly blocked in the presence of RSV. Furthermore, RSV significantly suppressed the phosphorylation of TLR4 downstream factors NF-κB p65, p38MAPK, and STAT3. Conclusion: RSV exerts protective effects against experimental periodontitis in db/db mice via negative regulation of TLR4 signaling.

show abstract

HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation

Cited by 147 publications

References 121 publications

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

TLR4-dependant pro-inflammatory effects of HMGB1 on human adipocyte

HMGB1, S100 proteins and other RAGE ligands in cancer - markers, mediators and putative therapeutic targets

Resveratrol ameliorates experimental periodontitis in diabetic mice through negative regulation of TLR4 signaling

Contact Info

Product

Resources

About